drug delivery volume issue 2014 [doi 10.3109%2f10717544.2014.891273] jain, akash; pandey, vikas;...
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http://informahealthcare.com/drdISSN: 1071-7544 (print), 1521-0464 (electronic)
Drug Deliv, Early Online: 1–6! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10717544.2014.891273
RESEARCH ARTICLE
Formulation and characterization of floating microballoons ofNizatidine for effective treatment of gastric ulcers in murine model
Akash Jain1, Vikas Pandey1, Aditya Ganeshpurkar2, Nazneen Dubey2, and Divya Bansal1
1Pharmaceutics Research Laboratory and 2Drug Discovery Laboratory, Shri Ram Institute of Technology-Pharmacy, Jabalpur,
Madhya Pradesh, India
Abstract
Background: The purpose of the present study was to formulate and characterize Nizatidine-encapsulated microballoons for enhancing bioavailability and increasing the residence time ofdrug in the gastrointestinal tract.Methods: Microballoons were prepared using emulsion solvent diffusion method using EudragitS-100 and HPMC as the polymer. The formulation process was optimized for polymer ratio,drug: polymer ratio, emulsifier concentration, stirring speed, stirring time. Optimizedformulation was subjected to scanning electron microscopy, drug entrapment, buoyancystudies, in-vitro drug release and in-vivo floating efficiency (X-ray) study. In-vivo antiulcer activitywas assessed by ethanol-induced ulcer in murine model.Results: The microballoons were smooth and spherical in shape and were porous in nature dueto hollow core. A sustained release of drug was observed for 12 h. Examination of thesequential X-ray images taken during the study clearly indicated that the optimized formulationremained buoyant and uniformly distributed in the gastric contents for a period of 12 h.In ethanol-induced ulcer model, drug-loaded Microballoon-treated group showed significant(p50.01) ulcer protection index as compared to free drug-treated group.Conclusion: Nizatidine-loaded floating microballoons may serve as a useful drug delivery systemfor prolonging the gastric residence time and effective treatment of gastric ulcers.
Keywords
Buoyancy, ethanol-induced ulcer,microballoons, nizatidine, X-rays
History
Received 18 January 2014Revised 2 February 2014Accepted 2 February 2014
Introduction
Oral administration suffer from the drawback of having
incomplete drug release from device and short residence time
of the pharmaceutical dosage form resulting in poor bioavail-
ability of drug in the gastrointestinal tract (GI) (Tayade &
Kale, 2007). Hence sustained release dosage forms have been
designed to both prolong gastrointestinal transit of the dosage
form as well as controlled drug release. Several gastrointes-
tinal targeting dosage forms (Moes, 1993; Deshpande et al.,
1997; Hwang et al., 1998), including intragastric flotation
systems (Yuasa et al., 1996; Rouge et al., 1998; Lee et al.,
1999), high-density systems (Hwang et al., 1998), mucoad-
hesive systems, adhesion to the gastric mucosal surface in
order to extend gastric residence time (GRT) (Akiyama et al.,
1995), magnetic systems (Groning et al., 1998), unfoldable,
extendible, or swellable systems (Fix et al., 1993) and
superporous hydrogel systems (Park, 1988), have been
developed.
One such approach is floating drug delivery systems
(FDDS) in which the system floats over the gastric contents
and drug is released slowly at the desired rate. These systems
can be used for drugs possessing solubility in acidic
environment and high rate of absorption in the upper part
of the small intestine (Deshpande et al., 1997; Arora et al.,
2005). Both single and multiple unit systems have been
developed. High variability of gastrointestinal transit time,
due to its all-or-nothing gastric emptying process is the
disadvantage associated with single unit system. Thus, a
multiple-unit floating system which distributes widely
throughout the GI has been developed. Sato et al. (2003)
developed a multiple-unit floating system involving hollow
microspheres (microballoons) with excellent buoyant proper-
ties using o/w emulsion solvent diffusion method.
Microballoons are in a strict sense, spherical empty particles
without core having internal hollow structure with air inside.
Microballoons incorporate a drug dispersed or dissolved
throughout particle matrix have the potential for controlled
release of drugs (Ojha et al., 2006).
Nizatidine is a histamine H2-receptor antagonist that
inhibits stomach acid production, and commonly used in the
treatment of peptic ulcer disease (PUD) and gastroesophageal
reflux disease (GERD). Nizatidine is absorbed from the upper
GI and is preferentially localized in parietal cells of gastric
mucosa. The short half-life (1–2 h) and rapid clearance of
nizatidine suggest it a rationale drug for gastroretentive drug
Address for correspondence: Dr. Divya Bansal, Associate Professor,Pharmaceutics Research Laboratory, Shri Ram Institute of Technology-Pharmacy, Jabalpur, Madhya Pradesh 482002, India. Tel: 0761-4001921.Fax: 0761-4001931. Email:[email protected]
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delivery. The high solubility, chemical and enzymatic stability
and absorption profile of nizatidine in acidic pH values
(of stomach), points to the potential of gastroretentive dosage
form. The present works aims to design gastroretentive drug
delivery system for nizatidine using microballoons as the
carrier system that could give site specific and controlled drug
release.
Materials and method
Nizatidine were obtained as gift samples from M/s
Dr Reddy’s Labs. Hyderabad. Eudragit S-100 was purchased
from Rohm Pharma. Gmbh, Germany and HPMC,
Dichloromethane, methanol, polyvinyl alcohol (PVA) and
Tween 80 were purchased from Central Drug House, Mumbai
(India). All other chemicals used were of analytical grade.
Preparation of microballoons
Microballoons were prepared using the emulsion solvent
diffusion method (Kawashima et al., 1992). Nizatidine (0.1 g),
polymers (1.0 g) and monostearin (0.5 g) were dissolved in a
mixture of dichloromethane (8 ml) and ethanol (8 ml) at room
temperature. Each solution was introduced into an aqueous
solution of PVA (0.75 w/v%, 200 ml) at 40 �C. Resultant
emulsion was stirred at 300 rpm with a propeller type agitator
for 1 h. The resulting polymeric spheres were dried overnight
at 40 �C.
The formulation process was optimized for polymer ratio,
drug: polymer ratio, emulsifier concentration, stirring speed,
stirring time (Table 1). On the basis of formulation and
process variables, the optimized conditions for preparation of
microballoons were recorded in Table 2.
Characterization of microballoons
Electron microscopy
Scanning electron microscopy (SEM, Jeon Scanning Electron
Microscpe J.S.-840) was performed to characterize the
surface of formed microspheres. The samples for SEM were
prepared by lightly sprinkling the microballoons on a double-
adhesive tape stuck to an aluminum stub. The stubs were then
coated with gold to a thickness of about 300 A under argon
atmosphere using a gold sputter module in a high-vacuum
evaporator. The samples were then randomly scanned using a
Scanning Electron Microscope and photomicrographs were
captured.
Entrapment efficiency
Microballoons containing drug equivalent to 100 mg
Nizatidine were digested in a 10 mL mixture of dichloro-
methane and methanol (1:1 v/v). The mixture was centrifuged
at 3000 rpm for 3 min and 1 ml of supernatant was withdrawn
and after suitable dilution with distilled water and assayed
spectrophotometrically. The percentage drug entrapment is
calculated from the equation given below.
% Entrapment Efficiency
¼
Amount of drug in
microballoons formulation
� �
Theoritical amount of
drug in the preparation
� � � 100:
In-vitro buoyancy
Microballoons (100 mg) were dispersed in USP dissolution
apparatus containing simulated gastric fluid (SGF 900 ml, pH
1.2, 37 �C) containing Tween 20 (0.02% w/v). It was stirred
with a paddle at 100 rpm for 12 h. After predetermined time
interval, the layer of floating particles was separated from
settled particle. Both fractions of particles were dried in
vacuum desiccators. Both the fractions of microballoons were
weighed and buoyancy was determined by using the formula:
Buoyancy ð%Þ ¼ Wf
Wf þWs
� 100:
where Wf and WS are the weights of the floating and sinking
microballoons, respectively.
In-vitro drug release study
The drug release study was carried out in USP paddle type
dissolution apparatus (Veego, DA-6DR USP). Microballoons
containing drug equivalent to 100 mg were gently spread over
the surface of 900 ml of dissolution media (SGF, pH 1.2). The
speed of rotation was maintained at 100 rpm and the
temperature of dissolution medium was thermostatically
controlled at 37 ± 2 �C. The samples were withdrawn at
suitable time interval from the dissolution apparatus. The
initial volume of fluid was maintained by adding fresh
Table 1. Process variables of nizatidine-loaded microballoons.
Formulationvariable
Particlesize (mm)
% Entrapmentefficiency
% Buoyancy(after 6 h)
Polymer ratio1:1 268.6 ± 4.6 51.4 ± 3.2 65.6 ± 3.41:2 272.4 ± 6.8 56.7 ± 2.8 79.4 ± 3.81:3 292.8 ± 4.3 65.4 ± 4.6 81.8 ± 2.81:4 308.5 ± 2.4 59.3 ± 3.8 73.4 ± 4.2
Drug:Polymer ratio1:1 266.6 ± 4.3 56.8 ± 3.6 65.2 ± 3.21:2 271.4 ± 6.2 60.6 ± 2.2 78.5 ± 4.51:3 290.5 ± 4.1 68.2 ± 4.2 85.6 ± 2.41:4 292.8 ± 1.4 68.2 ± 4.1 79.5 ± 2.8
Emulsifier concentration (%w/v)0.50 292.7 ± 3.3 67.6 ± 3.5 86.6 ± 2.80.75 284.2 ± 4.6 61.2 ± 4.8 84.3 ± 4.11.00 262.4 ± 3.6 59.6 ± 3.4 81.6 ± 2.21.25 249.6 ± 4.2 55.6 ± 2.8 72.8 ± 4.6
Stirring speed (rpm)300 304.4 ± 2.4 69.4 ± 1.2 80.4 ± 2.6500 290.2 ± 5.2 64.8 ± 4.2 83.64 ± 3.2700 274.6 ± 3.6 59.8 ± 5.2 74.8 ± 4.6
Table 2. Formula for the preparation of microballoonsafter optimization.
Optimized parameter Value
Polymer ratio 1:3Drug: polymer ratio 1:4Emulsifier concentration (%w/v) 0.5Stirring speed (rpm) 900Stirring time (hour) 3
2 A. Jain et al. Drug Deliv, Early Online: 1–6
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dissolution fluid after each withdrawal. The samples with-
drawn were assayed spectrophotometrically using UV–visible
spectrophotometer (Shimadzu 1701, Japan).
In-vivo floating efficiency (X-ray) study
The in-vivo study was carried out by administering floating
beads to rats and monitoring them by a radiological method
(Rajinikanth & Mishra, 2007) with slight modifications. Six
healthy albino rats of either sex, weighing 400–500 g were
used for the present study. The animals were housed in
individual cages, and the experiments were conducted in a
sanitized room at a temperature maintained at around 27 �C.
Food was withdrawn 12 h prior to the study with water ad
libitum. To make the beads radiopaque, 500 mg of barium
sulfate was incorporated into polymeric solution (the same
optimized formulation composition was used to prepare
radiopaque beads) and radiopaque beads were prepared
using a similar procedure to that mentioned in the preparation
of beads. Beads were administered through oral gastric tube
with 2 ml water in fasted state. The animals were not allowed
to eat or drink throughout the study (up to 6 h). In total, 1 ml
of water was administered to animals every hour throughout
the study. The position of bead in the rat’s stomach was
monitored by X-ray photographs (Siregraph-B, Siemens,
Germany) of the gastric region at varying time intervals
(at 1, 4 and 6 h). The protocol of the study was approved by
Animals Ethical Committee, Shri Ram Institute of
Technology-Pharmacy, Jabalpur, India (Protocol No: SRITP/
IEAC/12/05).
Antiulcer activity
This investigation was conducted on Albino rats, with an
average body weight of 400–450 g and ages up to 3 months.
Animals were kept in standard cages at constant room
temperature 25 ± 1 �C, with circadian rhythm (day/night), and
were fed standard laboratory rat feed. Before the experiment,
all animals were exposed to a 24-h fasting period prior to
treatment with alcohol, but had free access to water. Alcohol
stress was induced by intragastric administration of 1 ml of
100% alcohol (Arafa & Sayed-Ahmed, 2003). The animals
were divided into three groups, each consisting of five rats.
First group received normal saline. Nizatidine solution
(10 mg/ml) was administered orally to animals of second
group. Third group received nizatidine-loaded microballoons
(equivalent to 10 mg). Upon treatment, animals were
sacrificed, and the abdomen was opened by midline incision,
the stomach was removed, opened along the greater curvature,
rinsed gently with water, and pinned open for macroscopic
examination. Areas with gastric lesions were measured and
the ulcer index (UI) was estimated from the formula:
UI ¼ ½ulcerated area ðmm2Þ=total stomach area ðmm2Þ�:
Results
Formulation and optimization of microspheres
Floating microballoons were prepared by emulsion solvent
diffusion method using Eudragit S-100 and HPMC.
Formulations were optimized by using varying concentration
of Eudragit S-100 and fixed concentration of HPMC to
evaluate the effect of polymer concentration on the size of
microspheres. The mean particle size of the microballoons
significantly increased with increasing Eudragit S-100
concentration and was in the range of 268.6 ± 4.6 to
308.5 ± 2.4 mm (Table 1). Formulations were optimized in
terms of drug: polymer ratio; particle size of microballoon
ranged from 266.6 ± 4.3 to 302.8 ± 1.4 mm. Microballoons
was also optimized for varying emulsifier concentration
(% w/v). Mean particle size of microballoons was larger at
low concentration of emulsifier (0.5%; 293.7 ± 3.3 mm) and
it decreased with an increase in concentration of emulsifier
(1.25%; 249.6 ± 4.2 mm). An increase in stirring speed
(700 rpm) promoted formation of small sized microbal-
loons (274.6 ± 3.6). Table 2 demonstrates the optimized
formula.
Electron microscopy
Shape and surface morphology of microballoons was
observed by scanning electron microscopy (Figure 1) which
confirmed spherical shape and smooth surface of
microballoons.
Percent buoyancy
The buoyancy percentage for all batches almost was above
50% which was studied for 12 h.
In-vitro drug release study
In-vitro drug release studies were performed in simulated
gastric fluid pH 1.2 for 12 h. The in-vitro release profile was
biphasic with an initial burst release (16.05 ± 0.94%) upto
1.0 h which may be attributed to surface associated drug,
followed by a slower release phase as the entrapped drug
slowly diffused into the release medium (Figure 2).
Percentage of the drug released up to 12 h was 80.05 ± 0.64.
There was sustained release of drug at a constant rate.
In-vivo floating efficiency (X-ray) study
The optimized floating microspheres exhibited good in-vitro
buoyancy and controlled release behavior and hence was
finally selected for in-vivo radio graphical study. Examination
of the sequential X-ray images taken during the study clearly
indicates that the optimized formulation remained buoyant
Figure 1. SEM photomicrograph of nizatidine-loaded microballoons.
DOI: 10.3109/10717544.2014.891273 Nizatidine microballoons for gastric ulcers 3
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and uniformly distributed in the gastric contents for the study
period of 6 h (Figure 3).
Antiulcer activity
In ethanol-induced ulcer model, oral administration of 95%
ethanol in control group, produced characteristic lesions in
stomach which emerged as elongated bands of broad red
lesions. The in-vivo evaluation showed that UI values were
0.64 ± 0.08 for normal saline-treated group, 0.49 ± 0.11 for
nizatidine solution and 0.14 ± 0.08 for nizatidine microbal-
loons. Microballoons-treated group showed significant
(p50.01) ulcer protection index as compared to free drug-
treated group (Figure 4).
Discussion
Microballoons are one of the innovative gastroretentive drug
delivery systems. Their bulk density is less than density of
gastric contents which enables them to float in gastric fluid.
As microballoons float on gastric contents, drug is released at
a desired rate leading to maintenance of drug concentration
for a prolonged period of time. After the drug release is
completed, residual system is cleared off from the stomach.
Thus, such a system provides increased GRT and provides an
effective control over fluctuations in plasma drug
concentration.
Floating microballoons of nizatidine were prepared by
emulsion solvent diffusion method using Eudragit S-100 and
HPMC. Microballoons were prepared by using varying
concentration of Eudragit S-100 and fixed concentration of
HPMC. It is clear from Table 1 that formulation variables had
a great impact on buoyancy, particle size and entrapment
efficiency. On increasing Eudragit S-100 concentration, the
viscosity of the medium increased resulting in enhanced
interfacial tension. Shearing efficiency also diminished at
higher viscosities (Reddy et al., 1990). This resulted in
formation of larger sized particles.
Microballoons were prepared with different drug: polymer
ratio (1:1, 1:2, 1:3, 1:4), while other parameters were kept
constant. The mean particle size of the microballoons
increased significantly by decrease in drug polymer ratio.
The drug entrapment efficiency increased initially from
56.8 ± 3.6% to 68.2 ± 4.2% by the decrease in drug polymer
Figure 4. Evidence for the protective effect of nizatidine microballoons in rats treated with ethanol, (a) control group showing normal gastric integrity(b) nizatidine solution–treated group (100 mg/kg) (c) Nizatidine-loaded microballoons–treated group.
Figure 3. X-ray photographs of microballoons in the gastric region of rat after dosing of formulations in the fasted state: (a) before dosing, (b) 3 h afterdosing, (c) 6 h after dosing.
Figure 2. In-vitro release profile of optimized nizatidine microballoons(n¼ 3).
4 A. Jain et al. Drug Deliv, Early Online: 1–6
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ratio up to 1:3 after which it decreased. Since drug
entrapment, buoyancy and particle size are dependent on
factors like stirring speed and emulsifier concentration, an
increase in polymer concentration may have resulted in a shift
in the equilibrium between these factors, which was evident
by a reduction in drug entrapment and percentage buoyancy.
Thus, the optimized drug: polymer ratio was selected as 1:3.
The mean microballoon size, buoyancy and drug entrap-
ment efficiency were found to decrease with an increase in
emulsifier concentration. This may be due to the fact that
increase in emulsifier concentration resulted in increase in
miscibility of ethanol with dichloromethane (processing
medium), which may increase the extraction of drug into
the processing medium. The buoyancy could have decreased
due to tightening of polymeric network, leading to micro-
balloon shrinkage with an increase in concentration of
emulsifier. Increased degree of agitation (stirring) resulted
in formation of small sized microspheres.
Optimized formulation was subjected to in-vitro drug
release studies and floating behavior was observed by X-ray
studies. Shape of microballoons was examined by scanning
electron microscopy. Microballoons were distinguished as
spherical shape enfolded in hard polymer shell. Central cavity
of microballoons is formed due to volatilization of dichlor-
omethane. As the polymer and drug solution in dichloro-
methane and ethanol is dropped in PVA solution, ethanol
tends to diffuse in aqueous solution; this leads to formation of
a shell and produces a cavity within it which is produced due
to volatilization of dichloromethane. Such a phenomenon is
responsible for creating a buoyant and floating system that
tends to float in gastric fluid (Kawashima et al., 1991).
Buoyancy of microparticulate system is dependent on the
quantity of polymers, ratio of polymers and nature and type of
solvents used in formulation (Streubel et al., 2006). In the
current study, microballoons continuously floated over dis-
solution for more than 12 h. The buoyancy of microballoons
could be contributed due to presence of pores created due to
rapid evaporation of dichloromethane, by which air got
entrapped in pores allowing them to float.
Release of nizatidine from HPMC microballoons was
evaluated in SGF pH 1.2. A steady drug release (Figure 2)
from microballoons was observed, which could be due to
diffusion and erosion mechanism. This also demonstrated
‘‘no burst effect’’ from formulation as there was a progressive
drug release.
The success of any pharmaceutical formulation could be
assessed by biological studies. In the present work, ethanol-
induced ulcer model was utilized to determine efficacy of
nizatidine-loaded microballoons.
Ethanol produced gastric lesions which are due to stasis in
gastric blood flow which causes hemorrhage and tissue
necrosis. It rapidly penetrates gastric mucosa and plasma
membrane and enhances membrane permeability to water and
sodium which in turn augments massive calcium accumula-
tion. This proves to be a major step in pathogenesis of injury
of gastric mucosa (Halliwell & Gutteridge, 1987; Soll, 1990).
Along with it, when ethanol is metabolized in body, it causes
increased production of O�2 in tissues leading to increased
cellular free radical concentration, which are ultimately
responsible for breaking of DNA strands and protein
denaturation (Surendra, 1999). Nizatidine microballoons
efficiently inhibited ethanol-induced ulcers (Figure 4)
demonstrating its cytoprotective effect on gastric mucosa.
Conclusion
In-vitro data obtained for microballoons of nizatidine showed
excellent buoyancy. Microballoons of nizatidine floated in
SGF for a prolonged period of time and sustained drug release
from the beads over a period of 12 h. The in-vivo floating
efficiency of beads was satisfactory; beads were retained in
rat stomach for extended period. Thus, the microballoons may
prove to be promising candidate for obtaining stomach
specific drug delivery.
Acknowledgements
Authors are thankful to Rewa Shiksha Samiti for constant
support during studies.
Declaration of interest
The authors declare that there was no conflict of interest.
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